When agitating mesenchymal stem cells adhered on microcarriers in bioreactors, a compromise has to be found between sufficient particle suspension and limitation of hydromechanical stresses. The present study proposes a strategy to improve the design of an ‘elephant ear' impeller at the just‐suspended state by varying its relative size, blade slope angle, and position in the reactor. To do that, computational fluid dynamics simulations were coupled with multi‐objective optimization to minimize the hydromechanical stress encountered by the microcarriers. Two minimization criteria were considered: (P/V)@p and the energy dissipation function EDC. On the basis of 31 conditions, an optimal impeller geometry is proposed. A computational fluid dynamics‐based optimization strategy was developed to improve the design of an impeller for stem cell culture on microcarriers. Based on local integration of the turbulent energy dissipation rate within the bioreactor, two criteria were defined to minimize the hydromechanical stress encountered by the particles.